Secondary Metabolites Isolated from Chilean Marine Algae: A Review

Chile is in the extreme southwestern part of America, and it has an extreme length, of approximately 4300 km that increases to 8000 km considering the Chilean Antarctic Territory. Despite the large extent of its coastal territory and the diversity of geographic environments and climates associated with Chilean coasts, the research on marine resources in Chile has been rather scarce. From marine organisms found in Chilean coastal waters, algae have been the most studied, since they contain a wide range of interesting secondary metabolites that have some structural traits that make them unique and uncharacteristic. Thus, a wide structural variety of natural products including terpenoids (monoterpenes, sesquiterpenes, diterpenes, and meroterpenoids), furanones, and C15-acetogenins have been isolated and identified. This review describes the existing literature on bioprospecting and exploration of secondary metabolites from Chilean coasts.


Introduction
Marine natural products have served as a rich source of new bioactive agents [1][2][3]. The diversity of marine habitats and unique sea environmental conditions have enabled marine organisms to develop mostly untapped sources of potential drugs with superior chemical novelty [4]. During the last decades, much effort has been dedicated to isolating and identifying new compounds from marine organisms, with the interesting outcome that many of these derivatives exhibited biological activities [5][6][7][8][9][10]. Algae are one of the simplest organisms containing chlorophyll, and, therefore, are found in almost every place where there is light to perform photosynthesis, namely in seas, lakes, rivers, animals and plants (as symbiotic species) [11]. They can be found as colonies of single-celled or multicellular organisms, and in some cases collaborating as simple tissues. Consequently, their size varies from 3-10 µm (unicellular algae) to 70 m long, i.e., giant kelp species growing up to 50 cm per day. Algae are classified into two major groups: microalgae, found both in benthic environments (littoral) and in the ocean (phytoplankton), and macroalgae (marine algae) red, brown and green algae, established in the littoral zone [12]. Phytoplankton comprise organisms such as diatoms (Bacillariophyta), dinoflagellates (Dinophyta), green and yellow-brown flagellates (Chlorophyta; Prasinophyta; Prymnesiophyta, Cryptophyta, and Rhaphidiophyta) and blue-green algae (Cyanophyta). These photosynthetic organisms play an important role in the productivity of oceans and are at the base of the food chain [11]. algae, to name a few. The search criteria focused on algae obtained from Chilean coasts and the South Shetland Islands and reports of novel marine natural products. The latter were spectroscopically characterized and present interesting biological and pharmaceutical properties. Reports involving vegetable extracts or primary metabolites were omitted. If some contributions (works or results) were omitted, it was due to an unintended error that we deeply regret. The benthic habitat maps of continental Chile show special topographic characteristics that have joined with coastal currents and winds to enhance the spread of algae, and consequently, around 440 species have been identified [46]. Therefore, the study of Chilean algae is a challenging task, and they are probably a unique source of new compounds with interesting biological activities [47]. Thus, in this work we present a review of the literature on terpenes, C15-acetogenins, and furanones as secondary metabolites isolated from Chilean marine algae. Scifinder databases as well as the repositories of the Pontificia Universidad Católica de Chile and Universidad Técnica Federico Santa María were used to search reports published from 1967 to the present. Regarding the search methods, these involved filtering by authors, e.g., Blunt, J.W.; San-Martín, A.; Darias, J.; Silva, M.; Norte, M., as well as by keywords, e.g., secondary metabolites, brown algae, and red algae, to name a few. The search criteria focused on algae obtained from Chilean coasts and the South Shetland Islands and reports of novel marine natural products. The latter were spectroscopically characterized and present interesting biological and pharmaceutical properties. Reports involving vegetable extracts or primary metabolites were omitted. If some contributions (works or results) were omitted, it was due to an unintended error that we deeply regret.

Terpenoids
Chilean waters and coasts have turned out to be a fertile source of a variety of marine organisms from which new terpenes have been obtained. For instance, the terpenes shown in Figure 2 were isolated and identified from Trimusculus peruvianus, a marine mollusk collected near Antofagasta coast, Chile. Compound 5, identified as a new terpene, and previously reported compounds, 6 and 7 were assayed for their toxicity against Artemia saline [1,[48][49][50].

Terpenoids
Chilean waters and coasts have turned out to be a fertile source of a variety of marine organisms from which new terpenes have been obtained. For instance, the terpenes shown in Figure 2 were isolated and identified from Trimusculus peruvianus, a marine mollusk collected near Antofagasta coast, Chile. Compound 5, identified as a new terpene, and previously reported compounds, 6 and 7 were assayed for their toxicity against Artemia saline [1,[48][49][50].

Structural Features of Marine Terpenes
Some marine terpenes are known to have unique structural features. For instance, chamigrene [51], amphilectane [52], and cembrane [53] (Figure 3) exhibit unusual structures as well as uncommon functionalities, such as dichloroimine, isonitrile, isocyanate, isothiocyanate, and halogenated functions that are predominantly found in marine organisms. However, these functional groups are not exclusively marine [43]. as well as uncommon functionalities, such as dichloroimine, isonitrile, isocyanate, isothiocyanate, and halogenated functions that are predominantly found in marine organisms. However, these functional groups are not exclusively marine [43]. Some marine terpenes are known to have unique structural features. For instance, chamigrene [51], amphilectane [52], and cembrane [53] (Figure 3) exhibit unusual structures as well as uncommon functionalities, such as dichloroimine, isonitrile, isocyanate, isothiocyanate, and halogenated functions that are predominantly found in marine organisms. However, these functional groups are not exclusively marine [43]. Algae are frequently found in marine habitats, where they are exposed to environmental microorganisms. However, algae survive in these hostile environments, probably due to an inherently available chemical defense mechanisms. Therefore, many novel terpenes, such as monoterpenes [54], sesquiterpenes [55,56], diterpenes [57,58], meroterpenoids [59], and steroids [60,61], have been normally isolated from different seaweeds [62]. Hence, this review will be focused on terpenes isolated from marine algae collected in Chilean coasts, classified according to the number of carbon atoms present in their structural nuclei, and on their biological activities.

Monoterpenes
Monoterpenes with multiple halogen substitution and uncommon carbon ring structures have been obtained mainly from red algae (Rhodophyta), and from green and brown algae, as well. They can be linear or cyclic (even heterocyclic) compounds [62].

Linear Polyhydroxylated Monoterpenes
Linear polyhalogenated monoterpene (8) and three plocamenols A-C (9-11) (Figure 4), are new compounds that were isolated from P. cartilagineum [63,64]. Algae are frequently found in marine habitats, where they are exposed to environmental microorganisms. However, algae survive in these hostile environments, probably due to an inherently available chemical defense mechanisms. Therefore, many novel terpenes, such as monoterpenes [54], sesquiterpenes [55,56], diterpenes [57,58], meroterpenoids [59], and steroids [60,61], have been normally isolated from different seaweeds [62]. Hence, this review will be focused on terpenes isolated from marine algae collected in Chilean coasts, classified according to the number of carbon atoms present in their structural nuclei, and on their biological activities.

Monoterpenes
Monoterpenes with multiple halogen substitution and uncommon carbon ring structures have been obtained mainly from red algae (Rhodophyta), and from green and brown algae, as well. They can be linear or cyclic (even heterocyclic) compounds [62].

Linear Polyhydroxylated Monoterpenes
Linear polyhalogenated monoterpene (8) and three plocamenols A-C (9-11) (Figure 4), are new compounds that were isolated from P. cartilagineum [63,64].  Compound 10 contains a terminal bromohydrin, whereas 11 is the corresponding keto derivative. To verify the correct HMBC correlations, 11 was acetylated using acetic anhydride in pyridine, leading to compound 12 [64]. Compounds 9 and 10, along with costatol, are the first reported metabolites having a double bond conjugate bromohydrin [64]. Additionally, empirical rules based on 13 C and 1 H NMR spectroscopic analysis have been proposed to determine the regiochemistry and geometry of the 1,2-bromochloro vinyl portion. This is extremely relevant since it can be applied to any compound of natural or synthetic origin containing this functionality [65].
This structural feature was also found in two novel monoterpenes, 13 and 14, (Figure 4), isolated from P. cartilagineum. The effect of γ-substituents on chemical shifts of C-1 and H-1 of the 1,2-dihalo vinylic portion was observed and used to validate the previously reported empirical rules for determining regio-and stereochemistry of substituted vicinal vinyl dihalide [66]. Compound 10 contains a terminal bromohydrin, whereas 11 is the corresponding keto derivative. To verify the correct HMBC correlations, 11 was acetylated using acetic anhydride in pyridine, leading to compound 12 [64]. Compounds 9 and 10, along with costatol, are the first reported metabolites having a double bond conjugate bromohydrin [64]. Additionally, empirical rules based on 13 C and 1 H NMR spectroscopic analysis have been proposed to determine the regiochemistry and geometry of the 1,2-bromochloro vinyl portion. This is extremely relevant since it can be applied to any compound of natural or synthetic origin containing this functionality [65]. This structural feature was also found in two novel monoterpenes, 13 and 14, (Figure 4), isolated from P. cartilagineum. The effect of γ-substituents on chemical shifts of C-1 and H-1 of the 1,2-dihalo vinylic portion was observed and used to validate the previously reported empirical rules for determining regio-and stereochemistry of substituted vicinal vinyl dihalide [66].
Prefuroplocamioid (15) (Figure 4) was isolated from P. cartilagineum, collected along the coast of Chile. This compound has been considered as a precursor of furoplocamioids (see below, compounds 34 and 35) [65], suggesting that biosynthesis of the 1,2-bromochloro vinyl system occurs previously to oxetane ring formation of furoplocamioids.
Several known compounds, including fucoxanthin (16), α and β-carotene (17 and 18), cholesterol (19) and plocamenone (20) ( Figure 5) were isolated from the red algae, Ceramium rubrum, and spectroscopically characterized. The halogenated monoterpene 20 had been previously isolated and identified from the red algae Plocamium sp. [67]. keto derivative. To verify the correct HMBC correlations, 11 was acetylated using acetic anhydride in pyridine, leading to compound 12 [64]. Compounds 9 and 10, along with costatol, are the first reported metabolites having a double bond conjugate bromohydrin [64]. Additionally, empirical rules based on 13 C and 1 H NMR spectroscopic analysis have been proposed to determine the regiochemistry and geometry of the 1,2-bromochloro vinyl portion. This is extremely relevant since it can be applied to any compound of natural or synthetic origin containing this functionality [65].
This structural feature was also found in two novel monoterpenes, 13 and 14, (Figure 4), isolated from P. cartilagineum. The effect of γ-substituents on chemical shifts of C-1 and H-1 of the 1,2-dihalo vinylic portion was observed and used to validate the previously reported empirical rules for determining regio-and stereochemistry of substituted vicinal vinyl dihalide [66].
Prefuroplocamioid (15) (Figure 4) was isolated from P. cartilagineum, collected along the coast of Chile. This compound has been considered as a precursor of furoplocamioids (see below, compounds 34 and 35) [65], suggesting that biosynthesis of the 1,2-bromochloro vinyl system occurs previously to oxetane ring formation of furoplocamioids.

Cyclohexane Polyhalogenated Monocyclic Monoterpenes
Polyhalogenated monocyclic monoterpenes, 21-28 (see Figure 6), were identified from red algae Plocamium cartilagineum collected at different points on the central Chilean coast (La Herradura (IV Region), Montemar and El Tabo (V Region), La Boca and Punta de Perros (VI Region), and Pumillahue (Chiloé, X Region)). Mertensene (27) and violacene (28), two brominated compounds, were identified spectroscopically by comparison with authentic samples [68]. Polyhalogenated monocyclic monoterpenes, 21-28 (see Figure 6), were identified from red algae Plocamium cartilagineum collected at different points on the central Chilean coast (La Herradura (IV Region), Montemar and El Tabo (V Region), La Boca and Punta de Perros (VI Region), and Pumillahue (Chiloé, X Region)). Mertensene (27) and violacene (28), two brominated compounds, were identified spectroscopically by comparison with authentic samples [68]. A study carried out with samples of P. cartilagineum, collected in two different geographical areas (Quintay (V Region) and La Boca (VI Region)) showed very interesting results. The plant materials, divided into carposporophyte, tetraspomphyte and gametophyte-bearing plants, exhibited the same qualitative chemical composition but important quantitative differences for these three reproductive phases. Depending on their capacity to incorporate bromine, the collections were classified as α chemotype, terpenes with no A study carried out with samples of P. cartilagineum, collected in two different geographical areas (Quintay (V Region) and La Boca (VI Region)) showed very interest-ing results. The plant materials, divided into carposporophyte, tetraspomphyte and gametophyte-bearing plants, exhibited the same qualitative chemical composition but important quantitative differences for these three reproductive phases. Depending on their capacity to incorporate bromine, the collections were classified as α chemotype, terpenes with no bromine, and β chemotype, brominated monoterpenes. Compounds 21, 22 and 26 were identified only in La Boca samples, whereas compounds 27 and 28 were characteristic of Quintay samples, and compounds 23-25 ( Figure 6) were common to both collections [69]. The fungicide and insecticide/acaricide activities of several isolated derivates were determined; 28 showed the most potent insecticide activity among the compounds tested, mainly against Macrosteles facifrons [70].
Halogenated monoterpenes, 21-25 ( Figure 6), were also isolated from Shottera nicaensis, which was collected intertidally at La Boca (VI Region), Chile. The total amount of compounds isolated from S. nicaensis was one order of magnitude lower than that obtained from P. cartilagineum, i.e., 0.04% and 0.5% dry weight, respectively. Even though for both algae the mixture composition turned out to be identical, small changes in the relative composition were observed. Both algae grow together, but their morphology and taxonomy are so different that it is almost impossible to mix them up. Even more unlikely is the idea that algae belonging to two different families have a common enzymatic system that allows the elaboration of identical compounds of almost the same composition. These facts seem to agree with Crew's hypothesis about the algae Microcladia and Shottera growing in association with Plocamium, i.e., Microcladia and Shottera are able to concentrate the halogenated metabolites produced by Plocamium algae [71].

Tetrahydrofuran Monoterpenes
Tetrahydrofuran monoterpenes carrying non-common functional substituents, i.e., chloro or bromo vinyl groups, were identified in samples of P. cartilagineum collected off the central coast (V Region) of Chile. These compounds, 34-36 (Figure 9), are closely related to pantofuranoids obtained from the endemic Antarctic algae P. plocamioides, which indicates a close relationship between these species. The relative stereochemistry of these compounds was determined by spectroscopic experiments and molecular mechanics (MM2) calculations [75]. Compound 28 exhibited the greatest insecticidal activity, while 27 showed a moderate activity against Aphis fabae [73].

Tetrahydrofuran Monoterpenes
Tetrahydrofuran monoterpenes carrying non-common functional substituents, i.e., chloro or bromo vinyl groups, were identified in samples of P. cartilagineum collected off the central coast (V Region) of Chile. These compounds, 34-36 (Figure 9), are closely related to pantofuranoids obtained from the endemic Antarctic algae P. plocamioides, which indicates a close relationship between these species. The relative stereochemistry of these Tetrahydrofuran monoterpenes carrying non-common functional substituents, i.e., chloro or bromo vinyl groups, were identified in samples of P. cartilagineum collected off the central coast (V Region) of Chile. These compounds, 34-36 (Figure 9), are closely related to pantofuranoids obtained from the endemic Antarctic algae P. plocamioides, which indicates a close relationship between these species. The relative stereochemistry of these compounds was determined by spectroscopic experiments and molecular mechanics (MM2) calculations [75].

Tetrahydrofuran Monoterpenes
Tetrahydrofuran monoterpenes carrying non-common functional substituents, i.e., chloro or bromo vinyl groups, were identified in samples of P. cartilagineum collected off the central coast (V Region) of Chile. These compounds, 34-36 (Figure 9), are closely related to pantofuranoids obtained from the endemic Antarctic algae P. plocamioides, which indicates a close relationship between these species. The relative stereochemistry of these compounds was determined by spectroscopic experiments and molecular mechanics (MM2) calculations [75]. Two new related tetrahydrofuran halogenated monoterpenes, 37 and 38 (Figure 9), were isolated from P. cartilagenium, collected at El Quisco, in the V Region of Chile. Structural elucidation of these compounds has been reported [63] and indicates the presence of unusual vicinal vinyl dihalide, like that observed in furoplocamioids (A-C) (34)(35)(36).
In the same line, compounds 21, 22, 24, 27, 28, 31, and 34 have been tested for their cytotoxic activity on tumor cell lines CT26, SW480, HeLa and SkMel28 with several multidrug resistance mechanisms, and on mammalian non-tumor cell line CHO (Chinese Two new related tetrahydrofuran halogenated monoterpenes, 37 and 38 (Figure 9), were isolated from P. cartilagenium, collected at El Quisco, in the V Region of Chile. Structural elucidation of these compounds has been reported [63] and indicates the presence of unusual vicinal vinyl dihalide, like that observed in furoplocamioids (A-C) (34)(35)(36).
In the same line, compounds 21, 22, 24, 27, 28, 31, and 34 have been tested for their cytotoxic activity on tumor cell lines CT26, SW480, HeLa and SkMel28 with several multidrug resistance mechanisms, and on mammalian non-tumor cell line CHO (Chinese hamster ovary cells). Results showed that compound 31 presents selective activity against SW480 and HeLa cells. An analysis of cellular extracts posterior to incubation with the assayed compounds and rotenone (positive uptake control) showed intracellular accumulation of 22, 27, 31 and 34 [76].
On the other hand, the effect of photon flux density (PFD) and temperature on the relative growth rate (RGR) of P. cartilagineum and formation of three halogenated monoterpenes, 22, 27 and 28, has been assessed [77].

Sesquiterpenes
Sesquiterpenes isolated from seaweeds can be classified, according to their carbon skeletons, into the following groups: laurene, chamigrane, brasilane, bisabolene, cuparane, and others [62]. Additionally, sesquiterpenes isolated from red algae are characterized by an elevated number of halogenated substitutions. These compounds play important roles, such as to defend algae against predators, fouling organisms and pathogens, as well as reproduction and protection against UV radiation, and serve as allelopathic agents.
Laurencia (Rhodophyceae) is the marine macroalgae genus that represents the most important source of sesquiterpenes. The reasons for this are, in the first place, that algae belonging to this genus are extremely widespread in the world, mainly from tropical and subtropical regions; second, they present a notable ability to biosynthesize a diversity of structurally different sesquiterpenes with new skeletons, such as (seco)-or (9,10-friedo)chamigrane, (cyclo) perforane, guimarane, and poitane. Brown algae and green algae also partly contribute to marine sesquiterpenes. However, the presence of halogenated compounds is very unusual.
regions; second, they present a notable ability to biosynthesize a diversity of structurally dif-ferent sesquiterpenes with new skeletons, such as (seco)-or (9,10-friedo)-chamigrane, (cyclo) perforane, guimarane, and poitane. Brown algae and green algae also partly contribute to marine sesquiterpenes. However, the presence of halogenated compounds is very unusual.

Diterpenes
Diterpenoids are found in higher plants, insects, fungi, and marine organisms. Several of these compounds present antimicrobial, antitumor, cytotoxic, anti-inflammatory, antifungal, molluscicide, antifeedant, and antifouling activities [43]. With more than 40 species reported, the genus Dictyota has been presented as a powerful resource for diterpenic compounds with novel chemical structures. Cyclic diterpenes are produced by many members of this genus, just like typical diterpenes with a 6-methyl-5-hepten-2-yl side chain A. Three types of main carbon skeletons have been reported: dolabellanes (including dolastanes), xenicanes, and extended sesquiterpenes [62].

Xenicane Diterpenes
A new diterpene with xenicane skeleton, 59 ( Figure 12), has been obtained from Glossophora kunthii, collected at Valparaiso, Chile [82].  This new metabolite was fully characterized, including absolute stereochemistry. Other diterpenes, such as pachydictyol A and dictyotriol A C-12 monoacetate, were identified in this alga and their absolute configuration was determined by CD studies (exciton chirality method). These diterpenes are frequently isolated in the Dictyota genus [83].

Crenulides Diterpenes
Two new crenulide diterpenes, 60 and 61 ( Figure 13), have been obtained from the brown alga G. kunthii, collected at Horcones Bay, V Region, Chile. Their structures have been elucidated by spectral analysis and chemical correlation [84].

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This new metabolite was fully characterized, including absolute stereochemistry. Other diterpenes, such as pachydictyol A and dictyotriol A C-12 monoacetate, were identified in this alga and their absolute configuration was determined by CD studies (exciton chirality method). These diterpenes are frequently isolated in the Dictyota genus [83].

Crenulides Diterpenes
Two new crenulide diterpenes, 60 and 61 (Figure 13), have been obtained from the brown alga G. kunthii, collected at Horcones Bay, V Region, Chile. Their structures have been elucidated by spectral analysis and chemical correlation [84].

Meroterpenoids
Meroterpenoids are prenylated aromatic compounds of mixed biogenesis combining acyclic, monocyclic, and bicyclic terpenes with aromatic or substituted aromatic groups possessing different degrees of oxidation. Many meroterpenoids from seaweeds have interesting biological activities such as antibacterial, antiviral, and antifeeding properties [62]. Plants in the genera Humulus and Cannabis produce these metabolites [86].
Structural elucidation of 67 and 68 ( Figure 15) was carried out through spectroscopic analysis and theoretical studies. Remarkably, 67 was the first metabolite isolated from the Stypopodium genus that presents one halogen in its structure. At this point, it is worth noting that based on published NMR data of isoepitaondiol (64) (Figure 15), it was observed that the structure of compound 64 was wrongly assigned, and that the right structure of this compound corresponds to 65. The relative configuration of this compound was confirmed by single-crystal X-ray diffraction, while the absolute configuration was evidenced by vibrational circular dichroism in combination with DFT B3LYP/DGDZVP calculations [91].

Meroterpenoids
Meroterpenoids are prenylated aromatic compounds of mixed biogenesis combining acyclic, monocyclic, and bicyclic terpenes with aromatic or substituted aromatic groups possessing different degrees of oxidation. Many meroterpenoids from seaweeds have interesting biological activities such as antibacterial, antiviral, and antifeeding properties [62]. Plants in the genera Humulus and Cannabis produce these metabolites [86].
Seventeen meroterpenoids, 64-80 ( Figure 15), were isolated from alga Stypopodium flabelliforme, collected at Easter Island [87][88][89][90][91][92]. The epitaondiol (65) structure was fully revised, and a meroditerpenoid containing an unusual two fused six-membered rings forced into the twist-boat conformation was demonstrated [87]. Taondiol (76) (Figure 15) has been isolated previously from this Stypopodium species. The absolute configurations of (−)-taondiol diacetate (74) and (+)-epitaondiol diacetate (71) isolated previously were determined using vibrational circular dichroism (VCD). For verification, their relative stereochemistry was determined by X-ray diffraction. Additionally, the crystal stereo structure of meroditerpenoid (79) (Figure 15) was reported [92]. Insecticidal activities of compounds 65, 66 and 71 ( Figure 15) were tested, mainly against Spodoptera frugiperda, and 71 showed the highest anti-insect activity. On the other hand, compound 71 showed no activity towards the National Cancer Institute's test (U.S.A.) for agents active against HIV (killing of T lymphocytes by HIV) [88]. The inhibitory effects of 66 ( Figure 15) were studied. Additionally, the molecular action of this com- Structural elucidation of 67 and 68 ( Figure 15) was carried out through spectroscopic analysis and theoretical studies. Remarkably, 67 was the first metabolite isolated from the Stypopodium genus that presents one halogen in its structure. At this point, it is worth noting that based on published NMR data of isoepitaondiol (64) (Figure 15), it was observed that the structure of compound 64 was wrongly assigned, and that the right structure of this compound corresponds to 65. The relative configuration of this compound was confirmed by single-crystal X-ray diffraction, while the absolute configuration was evidenced by vibrational circular dichroism in combination with DFT B3LYP/DGDZVP calculations [91].
Insecticidal activities of compounds 65, 66 and 71 ( Figure 15) were tested, mainly against Spodoptera frugiperda, and 71 showed the highest anti-insect activity. On the other hand, compound 71 showed no activity towards the National Cancer Institute's test (U.S.A.) for agents active against HIV (killing of T lymphocytes by HIV) [88]. The inhibitory effects of 66 ( Figure 15) were studied. Additionally, the molecular action of this compound on microtubule assembly was also analyzed [89,90].
Compound 65 and sargaol (78) were tested on HCl/ethanol-induced gastric lesions in mice and compared with lansoprazole. Both 65 and 78 showed gastroprotective activity with ED 50 values between 35 mg/kg and 40 mg/kg. The results suggest that 65 and 78 protect the gastric mucosa in the HCl/EtOH model in mice [94].
Pacifenol (43) (Figure 10), stypotriol triacetate (79) and epitaondiol (65) (Figure 15) were assayed for their anti-inflammatory effects. Compound 65 showed an important topical anti-inflammatory activity, whereas the other compounds showed a non-significant effect. Compound 65 inhibited human recombinant synovial phospholipase A 2 activity in a concentration-dependent manner, whereas 40 effectively inhibited the degranulation response, but none of these compounds affected superoxide generation by human neutrophils [95].
Chilenone A (98) (Figure 19) was obtained from Laurencia chilensis, collected at Horcones Bay, Chile, and its structure was determined by spectroscopic and X-ray crystallographic techniques. The structure of 98 is unusual, and there are no previously reported
Chilenone A (98) (Figure 19) was obtained from Laurencia chilensis, collected at Horcones Bay, Chile, and its structure was determined by spectroscopic and X-ray crystallographic techniques. The structure of 98 is unusual, and there are no previously reported antecedents in this respect. The potential precursor, 2-methyl-3(2β)-furanone has been known since 1929, but it has not been reported previously from any natural sources [103]. Chilenone B (99) (Figure 19) was obtained from a posterior collection of the same algae and its structure was established by X-ray diffraction and spectroscopic experiments. Compound 99 was identified as a trimer of 2-methyl-3(2H)-furanone [104].
Mar. Drugs 2022, 20, x FOR PEER REVIEW 14 of 18 antecedents in this respect. The potential precursor, 2-methyl-3(2β)-furanone has been known since 1929, but it has not been reported previously from any natural sources [103]. Chilenone B (99) (Figure 19) was obtained from a posterior collection of the same algae and its structure was established by X-ray diffraction and spectroscopic experiments. Compound 99 was identified as a trimer of 2-methyl-3(2H)-furanone [104]. Finally, a new tetracyclic polyketal 100 ( Figure 20) was identified from the marine red alga L. chilensis, collected in Cocholgüe, Concepción Bay, VIII region, Chile. This compound was isolated from chloroform extract, recrystallized from ethyl acetate and finally characterized by X-ray diffraction [105].

Conclusions
A first review of investigations carried out with marine algae from the Chilean coasts was published in 1989. Herein, we have updated the information by compiling all works, published up to mid-2019, on natural products isolated from algae collected along the coasts of Chile. The main species of algae that have been studied are Plocamium cartilagineum, Shottera nicaensis, Pantoneura plocamioides, Ceramium rubrum, Laurencia claviformis, Laurencia chilensis, Dictyota crenulata, Glossophora kunthii, Desmarestia menziesii, Stypopodium flabelliforme, and Ptilonia magellanica. From the total number of marine natural prod- Finally, a new tetracyclic polyketal 100 ( Figure 20) was identified from the marine red alga L. chilensis, collected in Cocholgüe, Concepción Bay, VIII region, Chile. This compound was isolated from chloroform extract, recrystallized from ethyl acetate and finally characterized by X-ray diffraction [105].
Mar. Drugs 2022, 20, x FOR PEER REVIEW 14 of 18 antecedents in this respect. The potential precursor, 2-methyl-3(2β)-furanone has been known since 1929, but it has not been reported previously from any natural sources [103]. Chilenone B (99) (Figure 19) was obtained from a posterior collection of the same algae and its structure was established by X-ray diffraction and spectroscopic experiments. Compound 99 was identified as a trimer of 2-methyl-3(2H)-furanone [104]. Finally, a new tetracyclic polyketal 100 ( Figure 20) was identified from the marine red alga L. chilensis, collected in Cocholgüe, Concepción Bay, VIII region, Chile. This compound was isolated from chloroform extract, recrystallized from ethyl acetate and finally characterized by X-ray diffraction [105].

Conclusions
A first review of investigations carried out with marine algae from the Chilean coasts was published in 1989. Herein, we have updated the information by compiling all works, published up to mid-2019, on natural products isolated from algae collected along the coasts of Chile. The main species of algae that have been studied are Plocamium cartilagineum, Shottera nicaensis, Pantoneura plocamioides, Ceramium rubrum, Laurencia claviformis, Laurencia chilensis, Dictyota crenulata, Glossophora kunthii, Desmarestia menziesii, Stypopodium flabelliforme, and Ptilonia magellanica. From the total number of marine natural products identified (92)

Conclusions
A first review of investigations carried out with marine algae from the Chilean coasts was published in 1989. Herein, we have updated the information by compiling all works, published up to mid-2019, on natural products isolated from algae collected along the coasts of Chile. The main species of algae that have been studied are Plocamium cartilagineum, Shottera nicaensis, Pantoneura plocamioides, Ceramium rubrum, Laurencia claviformis, Laurencia chilensis, Dictyota crenulata, Glossophora kunthii, Desmarestia menziesii, Stypopodium flabelliforme, and Ptilonia magellanica. From the total number of marine natural products identified (92) The situation observed in the genus Plocamium is striking. The characteristic metabolites of this genus have been isolated from algae of the genera Microcladia, Shotera, Pantoneura and Ceramium. All of them belong to different families. So far, no explanation has been given for this phenomenon. On the other hand, it has been proposed that in P. violaceum, there would be two chemotypes depending on whether the monoterpenes are cyclic or lineal. An analogous situation can be described for P. cartilagineum; however, the description of oxygenated monoterpenes suggests that a possible chemotaxonomy of this species could become even more confusing.
Thus, from a chemical point of view, Chilean algae are characterized by the unique structures of some of their metabolites. However, considering the great variety of Chilean alga species, the number of works that have been published is relatively scarce. The extensive Chilean coasts are bathed by the cold Humboldt current, resulting in very cold waters in the extreme south and much warmer waters in the extreme north. Easter Island is a special case because it is in the middle of the ocean, far from the influence of this current and from any other kind of external influence. For these reasons, the marine biodiversity of the Chilean coast can be considered as an important source of new bioactive marine natural products that could be the basis for the development of new drugs but that have been poorly studied and exploited to date.